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Publication Abstract from PubMed

Modern infectious disease outbreaks often involve changes in host tropism, the preferential adaptation of pathogens to specific hosts. The Lyme disease-causing bacterium Borrelia burgdorferi (Bb) is an ideal model to investigate the molecular mechanisms of host tropism, because different variants of these tick-transmitted bacteria are distinctly maintained in rodents or bird reservoir hosts. To survive in hosts and escape complement-mediated immune clearance, Bb produces the outer surface protein CspZ that binds the complement inhibitor factor H (FH) to facilitate bacterial dissemination in vertebrates. Despite high sequence conservation, CspZ variants differ in human FH-binding ability. Together with the FH polymorphisms between vertebrate hosts, these findings suggest that minor sequence variation in this bacterial outer surface protein may confer dramatic differences in host-specific, FH-binding-mediated infectivity. We tested this hypothesis by determining the crystal structure of the CspZ-human FH complex, and identifying minor variation localized in the FH-binding interface yielding bird and rodent FH-specific binding activity that impacts infectivity. Swapping the divergent region in the FH-binding interface between rodent- and bird-associated CspZ variants alters the ability to promote rodent- and bird-specific early-onset dissemination. We further linked these loops and respective host-specific, complement-dependent phenotypes with distinct CspZ phylogenetic lineages, elucidating evolutionary mechanisms driving host tropism emergence. Our multidisciplinary work provides a novel molecular basis for how a single, short protein motif could greatly modulate pathogen host tropism.

Structural evolution of an immune evasion determinant shapes pathogen host tropism.,Marcinkiewicz AL, Brangulis K, Dupuis AP 2nd, Hart TM, Zamba-Campero M, Nowak TA, Stout JL, Akopjana I, Kazaks A, Bogans J, Ciota AT, Kraiczy P, Kolokotronis SO, Lin YP Proc Natl Acad Sci U S A. 2023 Jul 4;120(27):e2301549120. doi: , 10.1073/pnas.2301549120. Epub 2023 Jun 26. PMID:37364114^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.